This invention relates to the use of indole-3-aldehyde for treating immune dysreactive disorders, in particular of inflammatory and infectious diseases.
A large number of human diseases recognizes immune dysreactivity as a pathogenetic element which is exemplified, inter alia, in forms of acute and chronic hyper-inflammation (e.g., rheumatic ailments) and in autoimmune forms, i.e., activation of aberrant responses towards components of the human organism [1]. In many cases, the control of immune dysreactivity is purely symptomatic (e.g., as regards inflammatory disorders, by means of non-steroid anti-inflammatory drugs). This represents a serious therapeutic problem because it requires long-term treatments which can produce a series of, sometimes serious, side effects. As regards autoimmune forms, the functional meiopragia of the organ (e.g., the pancreas in type I diabetes) requires a costly daily substitutive therapy which strongly restricts the quality of the patient's life.
It is therefore of paramount importance to develop new treatment methods based on drugs that act with alternative mechanisms with respect to the mere control of symptoms and which interrupt the pathogenetic mechanisms, reversing or at least controlling the expression of the illness in the long term [2].
The growing understanding of the pathogenetic factors of many human illnesses, of both an infective and an inflammatory nature, permits foreseeing pathogenetic, if not etiologic operations, of the molecular type, aimed at optimizing the results of current therapies. The invention concerns the use of molecules, either endogenous or exogenous, that allow achieving this result.
In this direction, inventors have for some time been studying the possible transcriptional control of “anti-inflammatory” genes, i.e., which codify for endogenous proteins that permit immune homeostasis and therefore appear deficient or malfunctioning wherever an immune dysreactivity condition arises [3], [4].
Among the candidate genes that attract most attention is a group of genes regulated transcriptionally by a transcription factor known as receptor of aryl hydrocarbons, commonly known as AhR (acronym of Aryl Hydrocarbon Receptor) [5]. This transcription factor was initially identified as target and mediator of the activity of one of the most toxic xenobiotics, dioxin, but it has also shown itself capable of regulating the cell differentiation of a lymphocyte T population (regulator T cells) whose main function is precisely to control immune hyperactivity, including inflammation and autoimmunity [6].
The AhR is technically regulated by the ligand: in other words, in order to activate itself as transcriptional regulator, it must “encounter” molecules generally coming from the outside of the cell, often even of a xenobiotic nature.
Taking into consideration this group of genes, the inventors interested themselves in studying the role of the bacteria present in the intestine (and not only) of human beings (collectively known by the term Microbiota) in determining the state of health and illness, and more specifically, the role of such bacteria in infections and inflammatory disorders of the gastrointestinal tract.
The intestinal microbiota consists of hundreds of different bacterial species whose numerous metabolic activities affect the state of health. In fact, the intestinal microbiota takes part in the metabolism of carbohydrates, proteins and lipids, and regulates the secretion of hormones and the pH, as well as the production of compounds with anti-bacterial and immune modulation action [8], [9]. During the course of the evolution of the human species, an important and delicate balance has been created of mutual benefit to human beings and microflora, which however risks being compromised by sudden changes. In conditions of psycho-physical, food and environment stress, or after taking drugs, we assist in an imbalance of the microflora (dysbiosis) that makes the body susceptible to infections and illnesses such as obesity, intestinal inflammation (e.g., Crohn's disease and necrotizing entrocolitis) and tumours. Various factors influence the activities of intestinal microbiota, in both a positive and negative sense. Among these we can recall immune system tolerance, enzyme synthesis to use available nutrients, stress resistance, eating habits, antibiotic therapy, the host's genetic situation and chronic illnesses.
More in particular, the course of studies and experiments which have led to the invention are the following.
Studies in metagenomics (aimed at identifying quantity and quality of bacterial species) and metabolomics (aimed at identifying the bacterial metabolites produced) in the stomach and faeces of suitably selected mice have led to the discovery that commensal bacteria of the mouse and human intestine, in particular those known as lactobacilli, produce a new possible AhR ligand belonging to the family of indolic derivatives of the tryptophan metabolism. This is indole-3-aldehyde or indole-3-carbaldehyde (IAld, MF: C9H7NO, name IUPAC: IH-indole-3-carbaldehyde), the formula of which is shown below:

The identification of this new ligand was achieved starting with the knowledge of the fact that the endogen metabolites of tryptophan, which is a “food” of both human beings and their microbes, play a major role in the immunity homeostasis of the intestine of mammals, and with the consideration that, among the various metabolic paths used by intestinal bacteria, that of indolics seemed the most probable, taking into account the type of bacterium (i.e., lactobacilli) which were expanded in the intestine in conditions of abundance of tryptophan.
It is also underlined that, even though many AhR activator ligands are known belonging both to the animal and vegetable world [7], a ligand has never, on the other hand, been described which, originating from the prokaryotes, has functional activities in mammals, including therefore human beings.
This new possible AhR ligand having been identified, tests were performed to determine its capacity to effectively act as such. Such tests showed that the IAld appeared to have an agonist activity comparable or superior to that of other indolic ligands also deriving from the metabolism of the tryptophan, such as indole-3-acetaldehyde (IAAld), indole-3-acetic acid (IAA, Indole Acetic Acid), indole-3-lactic acid (ILA, Indole Lactic Acid), and have also shown that the AhR-agonist activity strictly depended on the dose. This has made it possible to come to the conclusion that IAld is in fact the prototype ligand of prokaryote origin that can interact with the AhR of the guest of mammals, including human beings.
A next step was aimed at understanding whether the interaction between IAld and AhR was functionally active. For this purpose, the transcription was assessed of genes usually transcribed following AhR activation. The examined genes included detoxification genes (in particular Cyp1A1 and CypB1) and codifying genes for proteins of an enzymatic or cytochemical nature, the translational potential of which is known in the field of the above-mentioned pathologies (anti-inflammatory genes), in particular IL-10 (interleuchin 10), IL-22 (interleuchin 22), IDO1 (Indole-ammine 2,3-dioxygenase 1) [8-10]. This evaluation has made it possible to determine that IAld produces, in a dose-dependent way, both the activation of the considered detoxification genes, above all in the colon, and, very important, the activation of the anti-inflammation genes both in the colon and in the stomach. It has therefore been demonstrated that IAld is able to “naturally” activate anti-inflammatory genes, i.e., which modulate the dysreactive process in its pathogenesis instead of only in its symptomatic expression, as is the case with current anti-inflammatory non-steroid drugs.
As the last step, the therapeutic potential of IAld was tested, by using experimental mice models in which the inflammatory dysreactive component was well known. For this purpose, experimental infection models were used from Candida albicans (which, as is known, is a commensal fungus of the oro-gastrointestinal tract, of the vagina and of the skin), whose inflammatory dysreactivity pathogenetic role is known, and a colitis model more frankly tied to an inflammatory/immunity dysregulation which involves, in this case too, IL-22, IL-10 and IDO1 [14],[15]. The data obtained from these experimental models showed that:                i) IAld was able to significantly reduce the growth of Candida albicans and that the therapeutic effect could not be found in the absence of AhR;        ii) at the same time, IAld produced, again in a way dependent on the presence of AhR, IL-22 and IL-10 in the examined infection models;        iii) a protective effect was also found in mice with colitis.        
The experimental results, which will be illustrated in greater detail later on, have therefore provided evidence that a protective mechanism implemented through the IAld/AhR/IL-22/IL-10 axis can be therapeutically useful in conditions of immune dysreactivity, distinguished by excessive inflammation and reduced immunologic tolerance.
Consequently, according to a first aspect of the invention, the use is proposed of indole-3-aldehyde in the medical field, in particular as a means of prevention and treatment for immune dysreactive disorders in those cases where the hyper-inflammatory component represents the basic element.